1. Field of the Invention
The invention relates to contrast or imaging agents useful in vivo for studies and diagnosis of the gastrointestinal tract. The agents are zeolite materials enclosing a paramagnetic ion such as trivalent gadolinium. The loaded zeolites are particularly suitable for oral administration and function well as magnetic resonance imaging contrast or image brightening agents in the upper gastrointestinal tract.
2. Description of Related Art
The availability of sophisticated methods such as MRI and CT has contributed to the increased use of imaging technology in therapy and diagnostic studies. Gastrointestinal tract imaging is a particular area of interest because currently used imaging agents generally provide poor imaging, resulting in visualization of little more than gross blockages or anatomical abnormalities.
Barium sulfate and paramagnetic iron oxide are agents traditionally used for gastrointestinal studies. The latter material has become popular because of the paramagnetic properties of Fe.sub.2 O.sub.3 which is suited for MRI studies, but it has many disadvantages. These include black bowel, side effects of diarrhea and, from an analytical standpoint most important, the presence of artifacts arising from clumping. When paramagnetic iron concentrates, it may become ferromagnetic, drastically altering its imaging properties. Even when images are obtained, the signal is black, making it difficult to distinguish imaged from nonimaged areas.
The development of imaging contrast agents, particularly for gastrointestinal tract studies has been slow. Historically, the most popular agent has been superparamagnetic iron oxide for magnetic imaging, due to its nonbiodegradability. Although good contrast effects have been achieved in some MR studies in the small bowel, increasing occurrence of blurring and `metal` artifacts in the distal part of the bowel has been recorded (1). In other studies with superparamagnetic iron oxide, good resolution of the head and tail of the pancreas, anterior margins of the kidneys and para-aortic region has been shown in human patients. Some patients experienced episodes of diarrhea (2).
Magnetic imaging is particularly useful for the study and diagnosis of tumors or inflammatory abdominal diseases. Paramagnetic species represented by gadolinium seem to be potentially agents for these studies, the metal itself cannot be used in humans because of its toxic properties. Nevertheless, diethylenetriamine penta-acetic acid (DTPA) complexes of trivalent gadolinium have less toxicity than the uncomplexed salt and have been tested in human patients. Opacification of the gastrointestinal tract has been reported, but less than 60% of the magnetic resonance scans showed improved delineation of abdominal pathologies. Furthermore, nearly 40% of the patients reported diarrhea and meteorism (3).
Encapsulation of solid paramagnetic complexes in sulfonated ion-exchange resins for use in abdominal imaging has been suggested. It has been speculated that such encapsulation in acid-stable materials would prevent significant demetallation which otherwise occurs in the stomach when image contrasting agents are orally administered for gastrointestinal tract imaging (4).
Superparamagnetic iron oxide has been coated onto a polymer carrier matrix and evaluated as an oral contrast medium for MRI. Generally good images were obtained in the region of the small bowel, except the duodenum, but the useful concentration range appeared to be fairly narrow since some concentrations caused an artifact in the stomach after ingestion of the agent (I).
There is clearly a need for orally effective, well-tolerated agents that can be used in humans for imaging studies. In particular, an MRI imaging agent applicable to gastrointestinal tract studies would be useful for visualizing the anatomy of the intestinal tract and particularly to differentiate normal and pathological states, such as tumors. An effective, orally deliverable paramagnetic imaging contrast agent devoid of the common side effects currently encountered with the presently used GI imaging agents would represent a significant improvement over the iron and gadolinium complexes described. These compounds have several problems, including toxicity and lack of good image quality. Even with reports of improved compositions such as carrier complexes and matrices, some areas of the intestine are inadequately visualized with these materials and side effects still exist. For example, although trivalent gadolinium is an excellent paramagnetic MRI contrast species, its toxicity limits use in humans to its DTPA complex, which itself may exhibit toxicity.
A solution to many of the problems inherent in the use of presently used agents of choice in imaging the gastrointestinal tract has been discovered. A nontoxic zeolite carrier that preferentially binds paramagnetic metal ions within a lattice-like structure has been shown to have little toxicity and to exhibit excellent imaging properties. Furthermore, many of the problems associated with the use of superparamagnetic iron oxide are eliminated, including metal imaging and patient side effects such as diarrhea.